AIMS: Neuroendocrine neoplasms (NNs) range from well to poorly differentiated and indolent to highly aggressive. The site of origin in metastatic NNs has therapeutic and prognostic implications. SATB2 is a transcriptional regulator involved in osteoblastic and neuronal differentiation and is a sensitive and specific marker of colorectal epithelium. This study aimed to evaluate the expression of SATB2 in NNs from various primary sites and its utility as a marker in determining the site of origin of these neoplasms. METHODS AND RESULTS: SATB2 immunohistochemistry was performed on 266 NNs, including lung small cell carcinomas (n = 39) and carcinoids (n = 30), bladder (n = 21) and prostate (n = 31) small cell carcinomas, and gastrointestinal (GI)/pancreatic NNs of various primary sites (n = 145) consisting of well-differentiated neuroendocrine tumours (WDNET)s (n = 124) and poorly differentiated neuroendocrine carcinomas (PDNEC)s (n = 21). SATB2 was expressed in prostatic (10 of 31, 32%) and bladder (eight of 21, 38%) small cell carcinomas, lung carcinoid tumours (one of 30, 3%), and lung small cell carcinomas (eight of 39, 21%). Among primary GI NNs, SATB2 was expressed in 37 of 124 (30%) WDNETs and four of 21 (19%) PDNECs. Of the former, 15 of 15 (100%) rectal/rectosigmoid and 22 of 22 (100%) appendiceal neoplasms expressed SATB2. Using receiver operator characteristic analysis, SATB2 was a sensitive and specific marker for rectal (100.0%, 80.0%) and appendiceal (100.0%, 84.5%) WDNETs, respectively. CONCLUSIONS: In summary, SATB2 is a sensitive and specific marker for rectal/rectosigmoid and appendiceal WDNETs, and may represent a useful diagnostic tool when these sites of origin are considered in the differential diagnosis.